Loss of the endothelial glucocorticoid receptor prevents the therapeutic protection afforded by dexamethasone after LPS

• Published in: PloS one Vol. 9; no. 10; p. e108126
• Main Authors: Goodwin, Julie E, Feng, Yan, Velazquez, Heino, Zhou, Han, Sessa, William C
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 09.10.2014; Public Library of Science (PLoS)
• Subjects: Activation; Animals; Anti-Inflammatory Agents - pharmacology; Apoptosis; Binding sites; Biology and Life Sciences; Cardiovascular disease; Cytokines; Dexamethasone; Dexamethasone - pharmacology; Drug dosages; Endocrinology; Endothelium; Endothelium - drug effects; Endothelium - metabolism; Experiments; Gene expression; Glucocorticoids; Glucocorticoids - metabolism; Hemodynamics; Inflammation; Interleukin 6; Interleukin-6 - metabolism; Kinases; Laboratory animals; Lipopolysaccharides; Lipopolysaccharides - pharmacology; Male; Medical research; Medicine; Medicine and Health Sciences; Mice; Mortality; NF-kappa B - metabolism; NF-κB protein; Nitric oxide; Nitric Oxide - metabolism; Nitric-oxide synthase; Pediatrics; Physical Sciences; Receptors, Glucocorticoid - metabolism; Sepsis; Sepsis - drug therapy; Sepsis - metabolism; Steroids; Studies; Tumor Necrosis Factor-alpha - metabolism; Tumor necrosis factor-α; United States > US; Connecticut
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0108126

Glucocorticoids are normally regarded as anti-inflammatory therapy for a wide variety of conditions and have been used with some success in treating sepsis and sepsis-like syndromes. We previously demonstrated that mice lacking the glucocorticoid receptor in the endothelium (GR EC KO mice) are extremely sensitive to low-dose LPS and demonstrate prolonged activation and up regulation of NF-κB. In this study we pre-treated these GR EC KO mice with dexamethasone and assessed their response to an identical dose of LPS. Surprisingly, the GR EC KO mice fared even worse than when given LPS alone demonstrating increased mortality, increased levels of the inflammatory cytokines TNF-α and IL-6 and increased nitric oxide release after the dexamethasone pre-treatment. As expected, control animals pre-treated with dexamethasone showed improvement in all parameters assayed. Mechanistically we demonstrate that GR EC KO mice show increased iNOS production and NF-κB activation despite treatment with dexamethasone.